What is the management approach for a patient with suspected Thrombotic Thrombocytopenic Purpura (TTP)?

Thrombotic Thrombocytopenic Purpura (TTP): Overview and Management

What is TTP?

TTP is a life-threatening thrombotic microangiopathy caused by severe deficiency (<10% activity) of ADAMTS13, the von Willebrand factor-cleaving protease, resulting in platelet-rich microthrombi that cause end-organ ischemia and damage. 1, 2

Pathophysiology

• ADAMTS13 deficiency allows ultra-large von Willebrand factor multimers to persist in circulation, leading to unchecked platelet aggregation and microvascular thrombosis. 3, 4
• The condition can be acquired (immune-mediated, ~90% of cases) due to anti-ADAMTS13 autoantibodies or congenital due to ADAMTS13 gene mutations. 5, 3
• Without ADAMTS13 to cleave these large multimers under high shear stress, platelet thrombi form throughout the microvasculature, causing tissue ischemia and infarction. 4

Clinical Presentation

The classic pentad (thrombocytopenia, microangiopathic hemolytic anemia, fever, renal dysfunction, neuropsychiatric symptoms) is present in only a minority of patients—do not wait for all five features before initiating treatment. 5

Key clinical features include:

• Severe thrombocytopenia (typically platelet count <30,000/µL) 2
• Microangiopathic hemolytic anemia with schistocytes on peripheral smear, elevated LDH, decreased hemoglobin, elevated indirect bilirubin, and low haptoglobin 2, 6
• Neurologic symptoms ranging from confusion to seizures or stroke 3
• Renal dysfunction (though typically milder than in hemolytic uremic syndrome) 5
• Fever may be present 5

Critical Diagnostic Workup

Immediate diagnostic testing must include peripheral blood smear to confirm schistocytes and ADAMTS13 activity level with inhibitor testing, but treatment must NEVER be delayed awaiting ADAMTS13 results. 1, 2

Essential initial laboratory tests:

• Peripheral blood smear (schistocytes are pathognomonic for microangiopathic hemolysis) 1, 2
• ADAMTS13 activity and inhibitor/autoantibody levels (draw before first plasma exchange but do not delay treatment) 1, 2
• Complete blood count, reticulocyte count, LDH, haptoglobin, indirect bilirubin 1, 6
• Coagulation studies (PT, aPTT, fibrinogen)—these should be normal or only mildly abnormal, distinguishing TTP from DIC 2, 6
• Creatinine, urinalysis 1, 6
• Direct antiglobulin test (typically negative in TTP) 2
• Blood type and antibody screen 1

Risk Stratification: PLASMIC Score

Use the PLASMIC score to identify intermediate-to-high risk patients (score ≥5) who require immediate empiric treatment before ADAMTS13 results return. 1, 2

PLASMIC score components (1 point each):

• Platelet count <30,000/µL 2
• Hemolysis variables present (reticulocyte count >2.5%, undetectable haptoglobin, or indirect bilirubin >2 mg/dL) 2
• No active cancer 2
• No history of solid-organ or stem-cell transplant 2
• MCV <90 fL 2
• INR <1.5 2
• Creatinine <2.0 mg/dL 2

A score ≥5 has high sensitivity for TTP and mandates immediate treatment. 1, 2

Immediate Management Protocol

First-Line Treatment: The Three Pillars

Initiate therapeutic plasma exchange (TPE) combined with high-dose corticosteroids and rituximab immediately when TTP is suspected—delay in treatment directly correlates with mortality. 1, 2, 6

1. Therapeutic Plasma Exchange (TPE)

• Begin daily TPE using fresh frozen plasma (1.0-1.5 plasma volumes) immediately upon suspicion of TTP. 1, 2
• Continue daily TPE until platelet count normalizes (≥150,000/µL) for at least 2 consecutive days, then taper frequency. 2, 6
• TPE both replenishes deficient ADAMTS13 and removes pathogenic autoantibodies and inflammatory cytokines. 3, 4
• For refractory cases, intensify to twice-daily plasma exchange sessions. 6, 7

2. High-Dose Corticosteroids

• Administer methylprednisolone 1 g IV daily for 3 days, with the first dose given immediately after the first TPE session. 1, 2, 6
• Following initial high-dose therapy, transition to prednisone 1-2 mg/kg/day and taper gradually based on clinical response. 1, 6
• Corticosteroids suppress autoantibody production and reduce inflammation. 5, 3

3. Rituximab (Anti-CD20 Monoclonal Antibody)

• Offer rituximab as part of initial therapy for acquired TTP (375 mg/m² weekly for 4 weeks). 1, 2
• Complete the full course of rituximab if initiated—this reduces relapse rates and improves long-term outcomes. 1
• Rituximab is effective in newly diagnosed cases, refractory cases, and for relapse prevention. 5, 3

Adjunctive Therapy: Caplacizumab

Consider caplacizumab (anti-von Willebrand factor nanobody) for patients with severe ADAMTS13 deficiency, particularly if ADAMTS13 activity is severely reduced with elevated inhibitor or anti-ADAMTS13 IgG levels. 1, 2, 6

• Caplacizumab inhibits platelet binding to von Willebrand factor, preventing microthrombi formation. 5, 3
• Discontinue caplacizumab if no exacerbation occurs within 3-5 days after stopping TPE. 1
• This agent reduces time to platelet normalization and decreases TTP-related complications. 5

Critical Management Pitfalls to Avoid

Transfusion Management

AVOID platelet transfusions unless life-threatening hemorrhage occurs—platelet transfusions may worsen thrombosis and increase mortality. 1, 2, 6

• Transfuse RBCs only the minimum necessary to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable patients. 1, 2
• Coordinate with blood bank before any transfusions. 1

Monitoring During Active Treatment

• Perform daily assessment of platelet count, hemoglobin, LDH, and clinical status during active TPE. 1
• Continue weekly monitoring of hemoglobin levels until steroid taper is complete. 1
• Monitor for treatment-related complications including line infections, citrate toxicity, and allergic reactions to plasma. 3

Management of Refractory TTP

For patients not responding to standard therapy (persistent thrombocytopenia or worsening hemolysis after 4-5 days of daily TPE), escalate treatment aggressively. 6, 7

Refractory TTP management options:

• Intensify plasma exchange to twice-daily sessions 6, 7
• Add or optimize rituximab dosing 6, 7
• Consider additional immunosuppression: cyclosporine, cyclophosphamide, vincristine, mycophenolate mofetil, or anti-thymocyte globulin 1, 6, 7
• Bortezomib (proteasome inhibitor) may be considered for severe refractory cases 3, 7
• Salvage splenectomy remains an option for truly refractory cases, though rarely needed with modern therapies 3, 7

Simultaneously rule out alternative diagnoses (atypical HUS, complement-mediated TMA, drug-induced TMA, malignancy-associated TMA) in refractory cases. 7, 4

Special Populations and Considerations

Pediatric TTP

In children, TTP is less common and plasma exchange can be deferred 24-48 hours until ADAMTS13 results confirm the diagnosis, as most pediatric thrombotic microangiopathy is Shiga toxin-associated HUS. 2

Secondary TTP

TTP can be secondary to systemic lupus erythematosus, HIV, HCV, malignancy, drugs (including immune checkpoint inhibitors), or transplantation—identify and address underlying triggers. 1, 3, 8

• In patients with systemic lupus erythematosus presenting with thrombotic microangiopathy, perform ADAMTS13 testing and comanage with an experienced hematologist. 1
• ICI-related TTP requires immediate recognition and treatment with TPE, corticosteroids, rituximab, and caplacizumab, with permanent discontinuation of the checkpoint inhibitor. 8

Congenital TTP

Congenital TTP due to ADAMTS13 gene mutations typically presents in childhood and requires different long-term management with prophylactic plasma infusions or recombinant ADAMTS13 (when available). 5, 3

Prognosis and Long-Term Management

• With prompt treatment, survival rates exceed 80-90%, but untreated TTP has mortality approaching 90%. 5, 3
• Relapse occurs in 30-50% of patients with acquired TTP, necessitating long-term follow-up. 3, 4
• Monitor for development of other autoimmune diseases, as TTP patients have increased risk. 3
• Assess for psychophysical sequelae including cognitive impairment, depression, and fatigue. 3
• High-titer ADAMTS13 inhibitors at presentation correlate strongly with high risk of relapsing disease. 4